5-Fluorouracil (5-FU) is a compound that has been utilized as an antitumor agent for a long time (Heidelberger C, Chaudhuri N K, Danenberg P V, Mooren D, et al. (1957) Fluorinated pyrimidines: a new class of tumor inhibitory compounds. Nature 179:663.666). The antitumor effects of 5-FU against various tumors have been reported.
The cytotoxic effect of 5-FU is based on the inhibition of DNA synthesis in cells. 5-FU inhibit even the DNA synthesis in non-tumor tissue not only that in tumor tissue. However, since usually a far more active DNA synthesis takes place in tumor tissues compared to non-tumor tissues, the manifested influence of the 5-FU-mediated inhibitory action is thought to be comparatively larger in tumor tissues. It is through this mechanism that 5-FU exerts an inhibitory action on tumor tissues.
On the other hand, the administration of 5-FU, which is a cytotoxic agent, often accompanies adverse effects that cannot be ignored. The cytotoxic effect of 5-FU disables not only tumor tissues, but also non-tumor tissues. 5-FU sensitivity in 5-FU administered patients is considered to be closely related to the magnitude of the adverse effects of the drug.
5-FU is a DNA synthesis inhibitor that targets thymidylate synthase. Thymidylate synthase catalyzes the intracellular conversion of deoxyuridylate to deoxythymidylate. Deoxythymidylate is the only de novo source of thymidylate, an essential precursor for DNA synthesis (Danenberg P V (1997) Thymidylate synthase a target enzyme in cancer chemotherapy. Biochim Biophys Acta 473:73.92).
The promoter of thymidylate synthase gene has been demonstrated to be polymorphic (Nobuyuki H, Masahiko C, Ryushi N, Keiichi T (1993) Characterization of the regulatory sequences and nuclear factors that function in cooperation with the promoter of the human thymidylate synthase gene. Biochim Biophys Acta 1216:409.416). Furthermore, it has been shown that the polymorphism of the thymidylate synthase gene promoter is related to the response of a subject towards 5-FU. Human thymidylate synthase gene has a polymorphism comprising two or three tandem repeats of a 28-bp sequence in its regulatory region. The expression level of the thymidylate synthase gene which is homozygous for three tandem repeats, is 3.6 times that of the thymidylate synthase gene which is homozygous for two tandem repeats. As a result, subjects carrying the three tandem repeats have significantly fewer adverse effects (Pullarkat, S T, Stoehlmacher J, Ghaderi V, Xiong Y, et al. (2001) Thymidylate synthase gene polymorphism determines clinical outcome of patients with colorectal cancer treated with fluoropyrimidine chemotherapy. Pharmacogenomics J 1:65.70).
Thymidylate synthase is an important target of not only 5-FU, but also other antitumor agents. For example, capecitabine, which was developed as an oral prodrug of 5-FU, also targets thymidylate synthase. This suggested that the polymorphism in the regulatory region of the human thymidylate synthase gene is a useful marker for determining the responsiveness of a subject towards antitumor agents.